PROJECT SUMMARY/ABSTRACT Deficiencies in the control of central nervous system (CNS) inflammation precipitate or exacerbate a plethora of debilitating neurodegenerative diseases, including Alzheimer?s disease (AD), yet our understanding of the mechanisms that regulate neuroinflammation is incomplete. Microglia, the distinctive tissue macrophages of the brain and spinal cord, display two coupled activities that are fundamental to the control of these diseases ? the regulated expression of neurotoxic proinflammatory cytokines and chemokines, and the phagocytosis of apoptotic cells and membranes. Multiple lines of evidence demonstrate that both of these coupled activities are controlled by signaling through TAM receptor tyrosine kinases. The experiments of this proposal address how the TAM receptors Axl and Mer (gene name Mertk) act to restrain disease in animal models of AD and Amyotrophic Lateral Sclerosis (ALS). In Aim 1, genetic and cell biological methods that exploit mouse mutants that develop AD-like and ALS-like disease will be used to quantify expression of TAM signaling components in the CNS and microglia with respect to amyloid burden, cytokine expression, and survival during the course of disease. In Aim 2, mice that carry germline mutations in TAM system genes (Axl, Mertk, Gas6, which encodes a TAM activator) will be crossed to the AD and ALS models in order to assess how the global loss of TAM signaling influences the course of disease. Tests will also be performed to assess the effects of clinically-relevant drugs that inhibit TAM receptor activity, or alternatively, boost TAM receptor expression, on AD development and progression. In Aim 3, cell-specific molecular genetic manipulations will be used to inactivate the Axl and Mertk genes specifically in microglia or brain vascular endothelial cells, at different stages of disease, to quantify the relative contribution of TAM action in these cell types to the control of AD. Together, these studies will delineate the molecular, cellular, and physiological features of a fundamentally new pathway of immune homeostasis in the CNS, and elucidate how TAM receptors and ligands may be exploited as new drug targets for therapeutic intervention in neurodegenerative disease.